Remedies or preventives for digestive diseases containing diaminotrifluoromethypyridine derivatives

ABSTRACT

A digestive system disease therapeutic or preventive agent containing as an active ingredient a diaminotrifluoromethylpyridine derivative represented by the formula (I) or its salt:  
                 
 
     wherein X is a —CW 1 R 1  group, a —COCOR 2  group, a —CW 1 NHCOR 2  group, a —C(═W 1 )W 2 R 3  group or a —CW 1 N(R 4 )R 5  group; Y is an alkyl group, a —CW 3 R 6  group, a —COCOR 7  group, a —NHCOR 7  group, a —C(═W 3 )W 4 R 8  group, a —(NH) m SO 2 R 9  group, a —(NH) m SO 2 OR 10  group or a —(NH) m SO 2 N(R 11 )R 12  group; each of R 1 , R 6  and R 9  is a chain hydrocarbon group, a monocyclic hydrocarbon group, a polycyclic hydrocarbon group, a monocyclic heterocycle group or a polycyclic heterocycle group; each of R 2  and R 7  is an-alkyl group, an alkoxy group, a phenyl group or a phenoxy group; each of R 3 , R 8  and R 10  is an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a phenyl group or a benzyl group; each of R 4 , R 5 , R 11  and R 12  is an alkyl group; each of W 1 , W 2 , W 3  and W 4  is an oxygen atom or a sulfur atom; and m is  0  or  1.

TECHNICAL FIELD

[0001] The present invention relates to a therapeutic or preventiveagent containing as an active ingredient adiaminotrifluoromethylpyridine derivative or its salt, useful fordigestive system diseases such as inflammatory bowel diseases, gastritisand peptic ulcer.

BACKGROUND ART

[0002] Japanese Patent No. 2762323 and U.S. Pat. No. 5,229,403 disclosethat a diaminotrifluoromethylpyridine derivative or its salt has aphospholipase A₂ inhibitory action and is useful as an active ingredientof an anti-inflammatory agent or an anti-pancreatitis agent. They alsodisclose that (1) phospholipase A₂ is secreted or activated in platletsor inflammatory cells by stimulations and contributes to the productionof a platlet activating factor (PAF) and arachidonic acid metabolites,(2) the arachidonic acid metabolites are closely related to variousdiseases, for example, inflammatory symptoms such as rheumaticarthritis, arthritis deformans, tendinitis, bursitis, psoriasis andrelated dermatitis; nasal and bronchial airway troubles such as allergicrhinitis and allergic bronchial asthma; and immediate hypersensitivereactions such as allergic conjunctivitis, (3) on the other hand,phospholipase A₂ secreted from pancreas is activated in the intestineand exhibits a digestive action, but once activated in the pancreas, itis believed to be one of the factors causing pancreatitis, and (4) theabove diaminotrifluoromethylpyridine derivative inhibits phospholipaseA₂ and thus is effective for treatment of diseases related tophospholipase A₂ such as inflammatory symptoms, nasal and bronchialairway troubles, immediate hypersensitive reactions or pancreatitis, andcan be used as an anti-inflammatory agent, an agent for treatingbronchial asthma, an anti-allergy agent, an anti-pancreatitis agent, ananti-nephritis agent or an anti-multiple organ failure agent.

[0003] Further, U.S. Pat. No. 5,492,908 discloses that such compoundscan be used as a therapeutic agent for rheumatoid arthritis, andJP-A-10-298076 discloses that some of these compounds are effective asan anticancer agent having a carcinogenesis inhibitory effect.

[0004] Among digestive system diseases, diseases for which newtherapeutic agents are particularly required, may, for example, beinflammatory bowel diseases, gastritis and peptic ulcer. Theinflammatory bowel diseases are meant for enteritis developed at smallintestine (including duodenum, jejunum and ileum) or large intestine(including cecum, colon and rectum), and they include enteritis, thecauses of which are clear, such as infectious enteritis, ischemicenteritis, radioenteritis, drug enteritis and irritable bowel syndrome,intractable inflammatory bowel diseases, the causes of crises of whichhave not been clear yet, such as ulcerative colitis (nonspecificidiopathic colitis), Crohn's disease (regional enteritis), Crohn'sdisease of large bowel (granulomatous colitis or regional colitis) andentero-Behcet's disease, and further include enteritis, not only thecauses of which have not been understood yet but also which themselveshave not been specified.

[0005] Human ulcerative colitis is nonspecific idiopathic inflammatorybowel disease which forms erosion or ulcer on lamina propria mucosa orsubmucosa of large intestine mucosa from rectum to cecum, and it hasconventionally been a relatively rare disease, however, the number ofpatients are rapidly increasing in recent years. As its clinicalsymptoms, characteristic pathognomonic findings such as diarrhea, bloodystool, abdominal pain and weight reduction may be mentioned, and it isan intractable disease with repetition of recurrence and remission. Itsdetailed cause and morbidity have not been clearly understood yet, butimmunopathological mechanism and psychological factor are considered tobe related. On the other hand, Crohn's disease is a disease whereininflammation is formed not only on the mucosa but on entire bowel walland non-diffusive and discontinuous lesion is formed on the entiredigestive canal from the mouth cavity to the anus, and its detailedcause of disease has not been understood yet. During progress of thedisease, in addition to denutrition, various serious digestive organ andparenteral symptoms such as intestinal stenosis, intestinal perforation,abdominal abscess and massive bleeding are likely to coincide, and therecurrence rate after operations is high with this disease.

[0006] As medical treatment for the ulcerative colitis, steroid hormone,Salazosulfapyridine (SASP) [Salazopyrin®, registered trademark] andmetronidazole [Flagyl®, registered trademark] are mainly used [NewEngland Journal of Medicine, vol. 25, p.1499 (1980), The Merck Manual,Seventeenth Edition, p.309, (1999)]. SASP used as the first choice drugparticularly for active ulcerative colitis at a minor to moderate stage,which is an azo compound of 5-aminosalicylic acid (5-ASA) andsulfapyridine, is effective only when lesion is present in the largeintestine, its effect is relatively weak at a severe stage, and it is inmany cases used together with another agent such as a steroid drug evenat a minor stage. Further, it is also pointed out that the effect isinsufficient at an acute stage of inflammation. Its detailed mechanismof action is still unclear in many points even though its variousactions have been reported such as prostaglandin synthesis inhibitoryaction, leukotriene synthesis inhibitory action, leukocyte chemotaxisinhibitory action, oxygen radical production inhibitory and erasingaction, immunosuppressive action and anti-inflammatory action. Further,by taking the drug, adverse reactions such as liver function failure,nausea and vomiting, headache, pyrexia, hemolytic anemia, malesterility, abdominal dysphoria, rash, lymph node swelling,granulocytopenia and folic acid deficiency appear, and the frequencyreaches 10 to 20% [Gastrointestinal Pharmacology, vol.21, p.643-658(1992)]. With a purpose of decreasing such adverse reactions, mesalazinewhich is a sustained release preparation coated so that 5-ASA is formedby the pH in the intestine has been developed and used clinically, butthe same problems as in the case of the above-described SASP have beenreported, and its effect does not exceed SASP [Japanese Pharmacology &Therapeutics, vol.22, p.93-121 (1994)]. On the other hand,adrenocorticosteroids such as Predonine or Rinderon have commonly beenused, however, on the other side of the therapeutic effect, otheradverse reactions due to virus and bacterial infection or suppression ofpituitary gland and adrenal cortex function have been pointed out asproblems [Sogo Rinsho (Comprehensive Clinic), vol.43, p.1725-1729(1994)], and because the prescription is very difficult, carefuladministration under hospitalization control is basically required. Astherapeutic agents effective for Crohn's disease, SASP, 5-ASA,mercaptopurine, adrenocorticosteroid and metronidazole may, for example,be mentioned, but none of them is considered to have a sufficientclinical effect.

[0007] In recent years, for such inflammatory bowel diseases, newtherapeutic agents such as a lipoxygenase inhibitor, a thromboxane A₂receptor antagonist, a thromboxane A₂ synthetase inhibitor, an oxygenradical removing agent, an interleukin 1 (IL-1) antagonist(JP-A-9-157182) and a neutralizing antibody against tumor necrosisfactor (TNF-α), and leukocytapheresis have been developed, however,development of more effective and safer therapeutic agents has beendesired.

[0008] On the other hand, digestive ulcer such as gastric ulcer orduodenal ulcer exhibits various symptoms depending upon the location ofthe ulcer and the age of the patient, and the main cause has classicallybeen considered as hypersecretion of gastric acid. As gastric acidhypersecretion inhibitors, H₂ blockers having a H₂ receptor antagonisticaction (such as cimetidine, ranitidine, famotidine, roxatidine acetateand nizatidine) and proton pump inhibitors (PPI: such as omeprazole andlansoprazole) have been used clinically. No one disputes that the curerate of gastric ulcer and duodenal ulcer was remarkably improved byappearance of these drugs, and these drugs are mainly used for thetreatment against digestive ulcer at present. However, many clinicalcases have been reported that even though the ulcer is temporarily curedby such a drug, the ulcer recrudesces with a high ratio so long asHelicobacter pylori is present in the digestive canal [New EnglandJournal of Medicine, vol.328, p.308 (1993)] as described hereinafter.Further, the incidence of digestive ulcer due to application of anonsteroidal anti-inflammatory agent tends to be high with patients whotake an H₂ blocker or PPI for a long period of time, such beingproblematic.

[0009] In recent years, it has been clarified that Helicobacter pyloriis an important pathogenic factor in crisis of gastritis, gastric ulcer,duodenal ulcer and stomach cancer [American Journal of Gastroenterology,vol.82, p.2283 (1987)], and a treatment with an antibacterial agent inaddition to a gastric acid secretion inhibitor has been applied toHelicobacter pylori positive digestive ulcer cases regardless of whetherit is initial crisis or recurrent crisis. There are various opinionswith regard to the action of Helicobacter pylori, and according to onetheory, it has been reported that urease produced by Helicobacter pyloriunder an acidic condition decomposes urea present in the stomach toproduce ammonia, and the produced ammonia directly impairs the gastricmucosa [Journal of Dairy Science, vol.67, p.481 (1984)]. As bacterialelimination treatment against Helicobacter pylori, various treatmentmethods employing mainly a bismuth preparation, an antibacterial agentor an antiprotozoan agent have been devised, however, no sufficientbacterial elimination effect can be obtained by single use of thesedrugs, and the treatment is carried out mainly by multiple drugcombination. For example, in Europe and U.S., classical three-drugcombination treatment with bismuth, metronidazole and tetracycline hasbeen carried out, and a bacterial elimination ratio of at least 90% canbe obtained, however, appearance of adverse reactions with highfrequency and complicated method of application lead to poor compliance,and such a treatment is not widely used in Japan. Further, two drugcombination treatment by PPI and an antibacterial agent such asamoxicillin or clarithromycin, or a short-term three drug combinationtreatment wherein omeprazole, clarithromycin and nitroimidazole in usualdosage are used together for one weak, have been developed. However,many cases where no stable bacterial elimination ratio can be obtainedor cases where recurrence takes place due to appearance of resistantbacterium, have been reported. Further, as application of anantibacterial agent in a large amount is required, it is hard forpatients to take the agent, and it is known that adverse reactions suchas diarrhea, nausea and vomiting occur in many cases, and such isgenerally known as a problem to be overcome.

[0010] Gastritis caused by impairment of the gastric mucosa are roughlyclassified into acute erosive gastritis, chronic erosive gastritis andnonerosive gastritis, postgastrectomy gastritis and other gastritissyndrome. The causes are various but many of them are in common with thecases of the above-described digestive ulcer, and the mainstream of thetreatment method at present is single or combination use of H₂ blockers,proton pump inhibitors and Helicobacter pylori elimination agents. Fromrecent studies, it has been reported that as novel therapeutic agentsfor digestive ulcer or gastritis, a digestive canal mucosa adherentanti-helicobacter pylori agent containing an antibacterial substance andan antiulcer substance (JP-A-7-126189, JP-A-10-167985), acholecystokinin antagonist (JP-A-8-259447), a mucin productionaccelerator containing lactoferrin as an active ingredient(JP-A-9-12473), an aminoalkylpyridyloxy derivative having both H₂receptor antagonistic action and gastric mucosa protective action(JP-A-11-92373), etc., are useful.

[0011] Further, JP-A-11-12171, JP-A-10-330346 and JP-A-10-101576disclose that a 1,4-benzodioxin derivative having a selective β₃receptor agonistic action, a straight chain nitron derivative having afree radical scavenging action and a drug containing Gricetin andglutamine (or a glutamine derivative) as active ingredients,respectively, are useful for treatment of various digestive systemdiseases, however, development of safer drugs having more excellenttherapeutic effects has been desired.

DISCLOSURE OF THE INVENTION

[0012] The present inventors have conducted extensive studies onpharmacological effects of diaminotrifluoromethylpyridine derivatives ortheir salts and as a result, found that these compounds have excellenttherapeutic effects on digestive system diseases such as inflammatorybowel disease, gastritis and peptic ulcer, and the present invention hasbeen accomplished on the basis of this discovery.

[0013] The present invention provides a therapeutic or preventive agentfor digestive system diseases, containing as an active ingredient adiaminotrifluoromethylpyridine derivative represented by the formula (I)or its salt:

[0014] wherein X is a —CW¹R¹ group, a —COCOR² group, a —CW¹NHCOR² group,a —C(═W¹)W²R³ group or a —CW¹N(R⁴)R⁵ group; Y is an alkyl group, a—CW³R⁶ group, a —COCOR⁷ group, a —NHCOR⁷ group, a —C(═W³)W⁴R⁸ group, a—(NH)_(m)SO₂R⁹ group, a —(NH)_(m)SO₂OR¹⁰ group or a—(NH)_(m)SO₂N(R¹¹)R¹² group; each of R¹, R⁶ and R⁹ which are independentof one another, is a chain hydrocarbon group which may be substituted, amonocyclic hydrocarbon group which may be substituted, a polycyclichydrocarbon group which may be substituted, a monocyclic heterocyclegroup which may be substituted or a polycyclic heterocycle group whichmay be substituted; each of R² and R⁷ which are independent of eachother, is an alkyl group which may be substituted, an alkoxy group whichmay be substituted, a phenyl group which may be substituted or a phenoxygroup which may be substituted; each of R³ , R⁸ and R¹⁰ which areindependent of one another, is an alkyl group which may be substituted,an alkenyl group which may be substituted, an alkynyl group which may besubstituted, a cycloalkyl group which may be substituted, a phenyl groupwhich may be substituted or a benzyl group which may be substituted;each of R⁴, R⁵, R¹¹ and R¹² which are independent of one another, is analkyl group which may be substituted; each of W¹, W², W³ and W⁴ whichare independent of one another, is an oxygen atom or a sulfur atom; andm is 0 or 1, excluding a case where one of X and Y is a —COCF₂X¹ group(wherein X¹ is a hydrogen atom, a halogen atom, an alkyl group or ahaloalkyl group), and the other is a —COCF₂X² group (wherein X² is ahydrogen atom, a halogen atom, an alkyl group, a haloalkyl group or analkylcarbonyl group), a —COOX³ group (wherein X³ is an alkyl group whichmay be substituted or a phenyl group which may be substituted) or a—COX⁴ group (wherein X⁴ is an alkyl group, a haloalkyl group, an alkenylgroup, an alkynyl group, a phenyl group which may be substituted, afuranyl group or a naphthyl group).

[0015] In the above formula (I), the above chain hydrocarbon group foreach of R¹, R⁶ and R⁹ may, for example, be an alkyl group, an alkenylgroup or an alkynyl group. The above monocyclic hydrocarbon group may bea cycloalkyl group, a cycloalkenyl group or a phenyl group. Thepolycyclic hydrocarbon group may, for example, be a condensed polycyclichydrocarbon group such as a naphthyl group, a tetrahydronaphthyl groupor an indanyl group, or a bridged polycyclic hydrocarbon group such asan adamantyl group, a noradamantyl group, a norbornanyl group or anorbornanonyl group, and the above monocyclic heterocycle group may, forexample, be a pyrrolyl group, a furanyl group, a thienyl group, apyrazolyl group, an imidazolyl group, an oxazolyl group, an isoxazolylgroup, a thiazolyl group, an isothiazolyl group, a thiadiazolyl group, apyrrolinyl group, a pyrrolidinyl group, a dihydrofuranyl group, atetrahydrofuranyl group, a dihydrothienyl group, a tetrahydrothienylgroup, a pyrazolinyl group, a hydantoinyl group, an oxazolinyl group, anisoxazolinyl group, an isoxazolidinyl group, a thiazolinyl group, athiazolidinyl group, a dioxolanyl group, a dithiolanyl group, a pyridylgroup, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, adihydropyridyl group, a tetrahydropyridyl group, a piperidinyl group, adihydrooxopyridazinyl group, a tetrahydrooxopyridazinyl group, adihydrooxopyrimidinyl group, a tetrahydrooxopyrimidinyl group, apiperazinyl group, a dihydropyranyl group, a tetrahydropyranyl group, adioxanyl group, a dihydrodithinyl group, a dithianyl group or amorphorinyl group. The above polycyclic heterocycle group may be acondensed polycyclic heterocycle group such as a thienothienyl group, adihydrocyclopentathienyl group, an indolyl group, a benzofuranyl group,a benzothienyl group, a benzoxazolyl group, a benzisoxazolyl group, abenzothiazolyl group, a benzimidazolyl group, a tetrahydrobenzothienylgroup, a dihydrobenzofuranyl group, a tetrahydrobenzisoxazolyl group, abenzodioxolyl group, a quinolinyl group, an isoquinolinyl group, abenzodioxanyl group or a quinoxalinyl group, or a bridged polycyclicheterocycle group such as a quinuclidinyl group.

[0016] The substituent for each of the chain hydrocarbon group which maybe substituted for each of R¹, R⁶ and R⁹, the alkyl group which may besubstituted and the alkoxy group which may be substituted for each of R²and R⁷, the alkyl group which may be substituted, the alkenyl groupwhich may be substituted and the alkynyl group which may be substitutedfor each of R³, R⁸ and R¹⁰, the alkyl group which may be substituted foreach of R⁴, R⁵, R¹¹ and R¹², and the alkyl group which may besubstituted for X³, may, for example, be a halogen atom, an alkoxygroup, a haloalkoxy group, an alkylthio group, a cycloalkyl group, acycloalkoxy group, a cycloalkenyl group, a cycloalkenyloxy group, analkoxycarbonyl group, an alkylcarbonyl group, an alkylcarbonyloxy group,an aryl group, an aryloxy group, an arylthio group, an amino group or anamino group substituted with an alkyl group. The number of suchsubstituents or substituents on such substituents may be one or more,and when the number is two or more, such substituents may be the same ordifferent.

[0017] Further, the substituent for each of the monocyclic hydrocarbongroup which may be substituted, the polycyclic hydrocarbon group whichmay be substituted, the monocyclic heterocycle group which may besubstituted and the polycyclic heterocycle group which may besubstituted for each of R¹, R⁶ and R⁹, the phenyl group which may besubstituted and the phenoxy group which may be substituted for each ofR² and R⁷, the cycloalkyl group which may be substituted, the phenylgroup which may be substituted and the benzyl group which may besubstituted for each of R³, R⁸ and R¹⁰, and the phenyl group which maybe substituted for X³, may, for example, be a halogen atom, an alkylgroup, a haloalkyl group, an alkoxy group, a haloalkoxy group, analkylthio group, a cycloalkyl group, a cycloalkoxy group, a cycloalkenylgroup, a cycloalkenyloxy group, an alkoxycarbonyl group, analkylcarbonyl group, an alkylcarbonyloxy group, an aryl group, anaryloxy group, an arylthio group, an amino group, an amino groupsubstituted with an alkyl group, a cyano group or a nitro group. Thenumber of such substituents or substituents on such substituents may beone or more, and when the number is two or more, such substituents maybe the same or different.

[0018] In the formula (I), the alkyl group and the alkyl moietycontained in each of X and Y may, for example, be C₁₋₁₈ alkyl such as amethyl group, an ethyl group, a propyl group, a butyl group, a pentylgroup, a hexyl group, a heptyl group, an octyl group, a decyl group or anonadecyl group, and they include linear or branched aliphaticstructural isomers. The alkenyl group and the alkenyl moiety containedin each of X and Y may be C₂₋₁₈ alkenyl such as a vinyl group, apropenyl group, a butenyl group, a pentenyl group, a hexenyl group, adecenyl group or a nonadecenyl group, and they include linear orbranched aliphatic structural isomers. The alkynyl group and the alkynylmoiety contained in each of X and Y may be C₂₋₁₈ alkynyl such as anethynyl group, a propynyl group, a butynyl group, a pentynyl group, ahexynyl group, a decynyl group or a nonadecynyl group, and they includelinear or branched aliphatic structural isomers. The cycloalkyl groupand the cycloalkyl moiety contained in each of X and Y may be C₃₋₈cycloalkyl such as a cyclopropyl group, a cyclobutyl group, acyclopentyl group, a cyclohexyl group or a cyclooctyl group. Thecycloalkenyl group and the cycloalkenylmoiety contained in each of X andY may be C₅₋₈ cycloalkenyl such as a cyclopentenyl group, a cyclohexenylgroup or a cyclooctenyl group. Further, the halogen atom contained ineach of X and Y may be a fluorine atom, a chlorine atom, a bromine atomor an iodine atom. The aryl group and the aryl moiety contained in eachof X and Y may, for example, be a phenyl group, a thienyl group, afuranyl group, a pyridyl group, a naphthyl group, a benzothienyl group,a benzofuranyl group or a quinolinyl group.

[0019] Now, preferred embodiments of the compounds of the presentinvention will be described. In the formula (I), it is preferred that Xis a —CW¹R¹ group or a —C(═W¹)W²R³ group and Y is a —SO₂R⁹ group. Eachof R¹ and R⁶ is preferably an alkyl group which may be substituted, analkenyl group which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted, a phenylgroup which may be substituted, a tetrahydronaphthyl group which may besubstituted, an indanyl group which may be substituted, a furanyl groupwhich may be substituted or a thienyl group which may be substituted;more preferably an alkyl group, a haloalkyl group, analkoxycarbonylalkyl group, an alkenyl group, a haloalkenyl group, acycloalkyl group, a cycloalkyl group substituted with a halogen atom, aphenyl group, a phenyl group substituted with a halogen atom, a phenylgroup substituted with an alkyl group or a haloalkyl group, a phenylgroup substituted with an alkoxy group or a haloalkoxy group, atetrahydronaphthyl group, an indanyl group, a furanyl group or a thienylgroup. Each of R² and R⁷ is preferably an alkoxy group which may besubstituted or a phenyl group which may be substituted; more preferablyan alkoxy group, a haloalkoxy group, a phenyl group or a phenyl groupsubstituted with a halogen atom. Each of R³, R⁸ and R¹⁰ is preferably analkyl group which may be substituted; more preferably an alkyl group ora haloalkyl group. Each of R⁴, R⁵, R¹¹ and R¹² is preferably an alkylgroup. R⁹ is preferably an alkyl group which may be substituted, analkenyl group which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted or a phenylgroup which may be substituted; more preferably an alkyl group, ahaloalkyl group, a phenyl group, a phenyl group substituted with ahalogen atom, a phenyl group substituted with an alkyl group or ahaloalkyl group or a phenyl group substituted with an alkoxy group or ahaloalkoxy group.

[0020] Preferred compounds among the compounds of the present inventionare compounds of the above formula (I) wherein X is analkoxycarbonylalkylcarbonyl group, an alkenylcarbonyl group, analkenylcarbonyl group substituted with a thienyl group, acycloalkylcarbonyl group, an indanylcarbonyl group, a furancarbonylgroup, a thiophenecarbonyl group, a tetrahydronaphthylcarbonyl group ora benzoyl group which may be substituted with a halogen atom or ahaloalkyl group, and Y is an alkylsulfonyl group. Specific compoundsincludeN-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-4-fluorobenzamide,N-(2-isopropylsulfonylamino-5-trifluoromethyl-3-pyridyl)-3-fluorobenzamide,N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-2-furancarboxamide,N-(2-isopropylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclopentanecarboxamide,N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide,N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-5-indanecarboxamide,N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)acetoxyacetamide,N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)crotonamide,N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-2-thiophenecarboxamide,N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-3-trifluoromethylbenzamide,N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)-3-fluorobenzamide,N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-6-(1,2,3,4-tetrahydronaphthalene)carboxamide,N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)crotonamide,N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-3-(2-thienyl)acrylamide,and their salts.

[0021] More preferred compounds may be compounds of the above formula(I) wherein X is a cycloalkylcarbonyl group, a furancarbonyl group or abenzoyl group which may be substituted with halogen, and Y is analkylsulfonyl group. Specific compounds includeN-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide,N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-4-fluorobenzamide,N-(2-isopropylsulfonylamino-5-trifluoromethyl-3-pyridyl)-3-fluorobenzamide,N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-2-furancarboxamideandN-(2-isopropylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclopentanecarboxamide,and their salts.

[0022] The compounds represented by the formula (I) may form a salt whenY is —SO₂R⁹ group (wherein R⁹ is as defined above). Such a salt may beany pharmaceutically acceptable salt, for example, an alkali metal saltsuch as a potassium salt or a sodium salt, an alkaline earth metal saltsuch as a calcium salt, or an organic amine salt such as atriethanolamine salt or a tris(hydroxymethyl)aminomethane salt. Such asalt may have crystal water.

[0023] The compounds represented by the formula (I) can be prepared, forexample, by a process as disclosed in Japanese Patent No. 2762323.Further, these compounds have geometrical isomers depending upon thetype of their substituents, and the present invention include isomers(cis-forms and trans-forms) and isomer mixtures.

[0024] The compounds of the present invention represented by the aboveformula (I) are useful as an active ingredient for a therapeutic orpreventive agent for digestive system diseases. Particularly, they areuseful as an active ingredient for a therapeutic or preventive agent forinflammatory bowel diseases such as ulcerative colitis (nonspecificidiopathic colitis), Crohn's disease (regional enteritis), largeintestine Crohn's disease (granulomatous colitis or regional colitis),entero-Behcet's disease, infectious enteritis, ischemic enteritis,radioenteritis, drug enteritis and irritable bowel syndrome, digestiveulcer such as gastric ulcer and duodenal ulcer, and gastritis. They areparticularly useful as an active ingredient for a therapeutic orpreventive agent for the above ulcerative colitis, Crohn's disease,large intestine Crohn's disease and entero-Behcet's disease, and theyare preferably used as an active ingredient for a therapeutic orpreventive agent for ulcerative colitis and Crohn's disease. Further,they are expected to be more effective by combination with another drugsuch as Chinese herbal remedy.

[0025] To administer the compound of the present invention as an activeingredient for a therapeutic drug for digestive system diseases such asulcerative colitis, Crohn's disease, gastric ulcer, duodenal ulcer andgastritis, it is formulated alone or together with a pharmaceuticallyacceptable carrier into a drug composition suitable for peroral orparenteral administration, such as a tablet, a powder, a capsule, agranule, an injection drug, an ointment, an inhalant, an enema or asuppository, and it is administered in the form of such a drugformulation. Further, in recent years, a drug formulation comprising asuppository base and a digestive canal mucosa adhesive matrix forperoral administration incorporated into the base, the matrix beingcapable of prolonging the retention time in the digestive canal to makethe active ingredient for a drug for gastric, duodenal, large intestine,small intestine or rectal ulcer affect over a long period of time at ahigh concentration with a high efficiency, utilizing adhesive propertyto the gastric mucosa or intestinal canal mucosa, has been reported(JP-A-5-132416, JP-A-7-330582), and administration employing it is alsopossible.

[0026] As a drug formulation suitable for peroral administration, asolid composition such as a tablet, a capsule, a powder, a granule or atroach; or a liquid composition such as a syrup suspension, may, forexample, be mentioned. The solid composition such as a tablet, acapsule, a powder, a granule or a troach may contain a binder such asfine crystalline cellulose, gum arabic, tragacanth gum, gelatine orpolyvinyl pyrrolidone; an excipient such as starch, lactose orcarboxymethyl cellulose; a disintegrator such as arginic acid, cornstarch or carboxymethyl cellulose; a lubricant such as magnesiumstearate, light silicic anhydride or colloidal silicon dioxide; asweetener such as sucrose; or a flavoring agent such as peppermint ormethyl salicylate. The liquid composition such as a syrup or asuspension may contain sorbitol, gelatine, methyl cellulose,carboxymethyl cellulose, a vegetable oil such as a peanut oil, anemulsifier such as lecithin as well as a sweetener, a preservative, acolorant or a flavoring agent, as the case requires. Such a compositionmay be provided in the form of a dried formulation. These formulationspreferably contain from 1 to 95 wt % of the active ingredient compound.

[0027] A drug formulation suitable for parenteral administration may,for example, be an injection drug. The injection drug may be prepared bydissolving the compound in the form of a salt in usual water forinjection, or may be formulated into a formulation suitable forinjection such as a suspension or an emulsion (in a mixture with amedically acceptable oil or liquid). In such a case, it may containbenzyl alcohol as an antibacterial agent, ascorbic acid as anantioxidant, a medically acceptable buffer solution or a reagent foradjusting the osmotic pressure. Such an injection drug preferablycontains from 0.1 to 8 wt % of the active ingredient compound.

[0028] A drug formulation suitable for topical or per rectaladministration may, for example, be an inhalant, an ointment, an enemaor a suppository. The inhalant may be formulated by dissolving thecompound of the present invention alone or together with a medicallyacceptable inert carrier in an aerosol or nebulizer solution, or may beadministered to the respiratory airway in the form of fine powder forinhalation. In the case of fine powder for inhalation, the particle sizeis usually not more than 50μ, preferably not more than 10μ. Such aninhalant may be used, if necessary, in combination with otherantiasthematic agent or bronchodilator.

[0029] An ointment may be prepared by a conventional method by anaddition of e.g. a commonly employed base. The ointment preferablycontains from 0.1 to 30 wt % of the active ingredient compound.

[0030] The suppository may contain a carrier for formulation which iswell known in this field, such as polyethylene glycol, lanolin, cacaobutter or fatty acid triglyceride. The suppository preferably containsfrom 0.1 to 95 wt % of the active ingredient compound.

[0031] The above drug compositions suitable for peroral, parenteral,topical or per rectal administration, may be formulated by known methodsso that after administration to a patient, the active ingredient will berapidly discharged, gradually discharged or belatedly discharged.

[0032] Needless to say, the dose of the compound of the presentinvention varies depending upon the type of the compound, theadministration method, the condition of the patient or the animal to betreated, and the optimum dose and the number of administration under aspecific condition must be determined by the judgment of a competentdoctor. Usually, however, a daily dose to an adult is from about 0.1 mgto about 10 g, preferably from about 1 mg to about 1 g. In the case ofthe above inhalation method, the dose of the compound of the presentinvention is preferably from about 0.01 mg to about 1 g peradministration.

[0033] Now, specific Formulation Examples of the therapeutic orpreventive agent of the present invention will be given. However, theformulation of the present invention is not limited thereto.

FORMULATION EXAMPLE 1 (Tablet)

[0034] (1) Active ingredient 20 mg (2) Lactose 150 mg  (3) Starch 30 mg(4) Magnesium stearate  6 mg

[0035] The above composition is tabletted so that the components (1) to(4) constitute one tablet.

FORMULATION EXAMPLE 2 )Powder, Subtilized Granule or Granule)

[0036] (1) Active ingredient 20 mg (2) Sugar ester (DK ester F-160,tradename, 180 mg  manufactured by DAI-ICHI KOGYO SEIYAKU CO., LTD.) (3)Surfactant (Dekagreen 1-L, tradename, 15 mg manufactured by NikkoChemicals Co., Ltd.) (4) Light silicic anhydride 25 mg

[0037] The above components (1) to (4) are mixed and formed into apowder, or subtilized granule or granule by granulation. Such a powder,subtilized granule or granule may be sealed in a capsule to obtain acapsule drug.

FORMULATION EXAMPLE 3 (Hard Gelatine Capsule Drug)

[0038] (1) Active ingredient 25 mg (2) Starch 200 mg  (3) Magnesiumstearate 10 mg

[0039] The above components (1) to (3) are packed in one hard gelatinecapsule to obtain a hard gelatine capsule drug.

FORMULATION EXAMPLE 4 (Injection Drug)

[0040] (1) Active ingredient  1 mg (2) Glucose 10 mg (3)tris(hydroxymethyl)aminomethane 2.16 mg  

[0041] A tris buffer containing the components (1) to (3) isfreeze-dried to prepare an injection drug.

FORMULATION EXAMPLE 5 (Ointment for External Skin Application)

[0042] (1) Active ingredient 0.5 g (2) White vaseline 25 g (3) Stearylalcohol 22 g (4) Propylene glycol 12 g (5) Sodium lauryl sulfate 1.5 g(6) Ethyl parahydroxybenzoate 0.025 g (7) Propyl parahydroxybenzoate0.015 g (8) Purified water 100 g

[0043] The components (1) to (8) are formulated into an ointment forexternal skin application by a usual method for preparation of anointment.

FORMULATION EXAMPLE 6 (Enema Formulation)

[0044] (1) Active ingredient 50 mg (2) Macrogol 400 2 g (3) Dipotassiumphosphate 141 mg (4) Potassium dihydrogenphosphate 44 mg (5) Methylparahydroxybenzoate 20 mg (6) Purified water 50 g

[0045] The active ingredient and methyl parahydroxybenzoate are added toMacrogol 400, followed by stirring to obtain a mixture, to which oneobtained by adding dipotassium phosphate and potassiumdihydrogenphosphate to the purified water is gradually added to preparean enema formulation.

FORMULATION EXAMPLE 7 (Suppository)

[0046] (1) Active ingredient   50 mg (2) Higher fatty acid glyceride1,650 mg

[0047] The component (1) is dispersed or dissolved in (2), and packedand sealed in a plastic container having a size appropriate as asuppository, followed by cooling for solidification to prepare asuppository.

FORMULATION EXAMPLE 8 (Rectum Remaining Suppository, Controlled ReleaseSuppository)

[0048] (1) Active ingredient  1 g (2) Witepsol W35 19 g

[0049] The component (1) is admixed with preliminarily heated anddissolved (2), and the admixture is packed and sealed in a plasticcontainer having a size appropriate as a suppository, followed bycooling for solidification to prepare a suppository.

EXAMPLES Test Example 1

[0050] As an ulcerative colitis model, trinitrobenzenesulfonic acid(TNB) is usually used, but as a drug effect evaluation system toaccomplish the present invention, a rat sodium dextran sulfate (DSS)induced ulcerative colitis model was used. It has been well known thatsaid model is considered as an experimental model similar to humanulcerative colitis from many viewpoints such as inhibision of weightgain, presence or absence of bloody stool, symptoms of e.g. anemia andformation of erosion at the large intestine, and no formation of lesionin the small intestine [FOLIA PHARMACOLOGICA JAPONICA vol. 105, p.145-152(1995)]. A therapeutic effect ofN-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamidesodium salt monohydrate (hereinafter referred to as compound 1) over thetest system was examined.

[0051] The compound 1 was used as a drug formulation. The formulationcomposition (content per one vial) was as follows. (a) Compound 1 (asanhydride) 100 mg (b) Mannitol (manufactured by KYOWA HAKKO 100 mg KOGYOCO., LTD.) (c) Tris(hydroxymethyl)aminomethane 21.6 mg  (manufactured byJUNSEI CHEMICAL) (d) Hydrochloric acid (manufactured by optimum amountSANKYO KAGAKU) (e) Sodium hydroxide (manufactured by optimum amountNippon Rika) (f) Distilled water  10 ml pH 8.7 ± 0.5

[0052] (1) Ulcerative Colitis Induction Method

[0053] A 3% aqueous solution of sodium dextran sulfate (DSS:manufactured by Wako Pure Chemical Industries, Ltd.) was put in adrinking bottle, and rats [Crj: CD(SD), male, Charles River Japan, 7weeks old when subjected to the test] were made to drink the solutionfreely for 11 days to cause colitis. After eleven days, rats whichsatisfied selection standards (among rats which discharged bloody stoolcontinuously for at least two days including the selection day, oneshaving a weight loss at the selection day of less than 20 g as comparedwith the weight on the previous day and having a hemoglobinconcentration of at least 12 g/dl) were selected, and divided intogroups (ten rats/group) so that there would be no difference in theaverage weight among groups.

[0054] With respect to a non-treated group and groups treated with thecompound 1, the 3% aqueous solution was changed to a 1% DSS aqueoussolution at the day of division, and the rats were made to drink thesolution freely for 14 days. Further, to the rats in the groups treatedwith the compound 1, the compound 1 was perorally administered once aday for 14 days from the day of division by means of a peroral sonde(dosage: 10 ml/kg). To the rats in the non-treated group and a normalgroup, distilled water for injection (manufactured by OtsukaPharmaceutical Co., Ltd.) alone was perorally administered similarly.Here, the normal group rats were made to drink distilled water forinjection freely instead of the DSS aqueous solution from initiation ofthe test to the day of anatomy.

[0055] A 10 mg/ml aqueous solution of the compound 1 was prepared byusing distilled water for injection (manufactured by OtsukaPharmaceutical Co., Ltd.) and administered to the rats in a desireddosage.

[0056] (2) Evaluation Method

[0057] Length of Large Intestine and Erosion Area of Large IntestineMucosa

[0058] Immediately after collection of blood, the large intestine (colonand rectum) was excised, and its length was measured by means of a rulerin a sufficiently relaxed state.

[0059] Immediately after the measurement, a fixing liquid was injectedinto the intestine, and the intestine was temporarily fixed for at least1 hour in such a state that the lumen was approximately uniformlyexpanded. Then, the intestinal canal was dissected along the mesenteriumadhered portion, and the intestine was completely fixed in an expandedstate in a 10% neutral buffering formalin aqueous solution for at leastone week. The intestine was washed with running water for about 5minutes, and further washed with purified water three times, and thenimmersed in a 3% aqueous acetic acid solution for about 5 minutes as apretreatment. Then, the intestine was immersed in a 1% Alcian blue(manufactured by Nacalai Tesque) (dissolved in a 3% aqueous acetic acidsolution) and dyed for about 20 minutes, and then washed with a 3%aqueous acetic acid solution from 4 to 5 times until elution of Alcianblue disappeared. By this operation, the large intestine was dyed inblue with graduation, and the erosion portion was dyed in deep blue, andthe area of the portion was analyzed by means of an image analyzer(general purpose image processing “WinROOF, Version 3.1”, manufacturedby MITANI CORPORATION) to obtain an erosion area.

[0060] The erosion suppression rate of the groups treated with thecompound 1 was obtained taking the erosion area of the non-treated groupas 100.

Erosion suppression rate (%)=[1−(average of erosion area of the groupstreated with the compound 1/average of erosion area of the non-treatedgroup)]×100

[0061] Histopathological examination: The large intestine, spleen,mesenterium and mesenteric lymph node, and femur bone marrow were fixedwith a 10% neutral buffering formalin aqueous solution [prepared byusing formalin (manufactured by Kishida Chemical Co., Ltd.), disodiumhydrogen phosphate (manufactured by Wako Pure Chemical Industries, Ltd.)and sodium dihydrogen phosphate dihydrate (manufactured by Wako PureChemical Industries, Ltd.)], and a histopathological preparation havinghematoxylin-eosin (manufactured by MERCK & CO., INC.) bichrome stainapplied thereto in accordance with a conventional method was preparedand subjected to microscopic examination (by means of BX50, manufacturedby OLYMPUS OPTICAL CO., LTD.).

[0062] (3) Results

[0063] Erosion area of large intestine: The compound 1 was perorallyadministered once a day over 2 weeks in a dose of 100, 10 or 1mg/kg/day, and as a result, a suppression rate of 62, 56 or 45% in alarge intestine erosion area as compared with the non-treated group wasshown, and remarkable erosion suppression effect was confirmed (Table1). Non erosion in large intestine was confirmed in the normal group.TABLE 1 Effect on erosion area Dose of Erosion Significant test compound1 suppression rate (non-treated group (mg/kg/day) (%) v.s. treatedgroup) 100 62 P < 0.01 (Williams test) 10 56 P < 0.01 (Williams test) 145 P < 0.05 (Williams test)

[0064] Length of large intestine: Further, it was also shown fromstudies on the length of the large intestine that the compound 1decreases intestine wall hyperplasia which is an accessory lesion of theerosion, and decreases anemia as a result of melena due to the erosion.

[0065] Histopathological study: As a result of histopathologicalstudies, a remarkable decrease of inflammation at the submucosa in theerosion formed region was confirmed in the groups treated with thecompound 1. Further, it was confirmed that normal tissue reconstructionby regeneration of the mucosa took place, and the strength and functionas the mucosal tissue tended to be restored.

Test Example 2

[0066] Therapeutic Effect on Trinitrobenzene Sulfonic Acid (TNBS)Induced Rat Crohn's Disease Model

[0067] The therapeutic effect of the compound 1 on TNBS induced ratCrohn's disease model was studied by the following method.

[0068] (1) SD male rats (12 weeks old) were anesthetized with Nembutaland their abdomen was opened up, a TNBS solution (TNBS 160 mg/mlethanol) was administered in 1 ml/kg in the colon located 10 cm belowthe ileocecum, and their abdomen was closed to prepare models, whichwere divided into a non-treated group and a group treated with thecompound 1, each group consisting of 6 rats. No such a treatment wascarried out for normal group rats. After preparation of the models, adrug formulation of the compound 1 of Test Example 1 diluted withdistilled water was perorally administered to rats of the group treatedwith the compound 1 once a day for 7 days in a dosage of 10 mg/kg/day ascalculated as anhydride of the compound 1. After completion ofadministration period, visual change, small intestine weight and mucosalmyeloperoxidase activity in small intestine (mucosal MPO activity) wereobserved or measured. The visual change was evaluated by digitizing andcompiling various changes. The ratio of the small intestine weight tothe body weight was also calculated from the small intestine weight andthe body weight. The results are shown in Table 2. TABLE 2 Examinationresults Small Ratio of small Mucosal intestine intestine to Visual MPOweight body weight score activity Group n Mean SD Mean SD Mean SD MeanSD Normal 6 1.11 0.12 0.0030 0.0003 1.5 0.8 0.48 0.22 group Non-treated6 2.18 0.45 0.0065 0.0009 7.8 0.8 8.93 3.71 group ## ### ## ## Treated 51.63 0.21 0.0042 0.0005 4.2 0.4 0.89 0.05 group * *** ** **

[0069] In the non-treated group, increase in values of the smallintestine weight, the ratio of the small intestine to the body weight,the visual score and the mucosal MPO activity was confirmed, and aninflammatory reaction and tissue impairment in the small intestine wereconfirmed. It was shown that in the group treated with the compound 1,increase in such examination values was suppressed, and the inflammatoryreaction and tissue impairment in the small intestine were decreased.

1. A therapeutic or preventive agent for digestive system diseases,containing as an active ingredient a diaminotrifluoromethylpyridinederivative represented by the formula (I) or its salt:

wherein X is a —CW³R¹ group, a —COCOR² group, a —CW¹NHCOR² group, a—C(═W¹)W²R³ group or a —CW¹N(R⁴)R⁵ group; Y is an alkyl group, a —CW³R⁶group, a —COCOR⁷ group, a —NHCOR⁷ group, a —C(═W³)W⁴R⁸ group, a—(NH)_(m)SO₂R⁹ group, a —(NH)_(m)SO₂OR¹⁰ group or a—(NH)_(m)SO₂N(R¹¹)R¹² group; each of R¹, R⁶ and R⁹ which are independentof one another, is a chain hydrocarbon group which may be substituted, amonocyclic hydrocarbon group which may be substituted, a polycyclichydrocarbon group which may be substituted, a monocyclic heterocyclegroup which may be substituted or a polycyclic heterocycle group whichmay be substituted; each of R² and R⁷ which are independent of eachother, is an alkyl group which may be substituted, an alkoxy group whichmay be substituted, a phenyl group which may be substituted or a phenoxygroup which may be substituted; each of R³, R⁸ and R¹⁰ which areindependent of one another, is an alkyl group which may be substituted,an alkenyl group which may be substituted, an alkynyl group which may besubstituted, a cycloalkyl group which may be substituted, a phenyl groupwhich may be substituted or a benzyl group which may be substituted;each of R⁴, R⁵, R¹¹ and R¹² which are independent of one another, is analkyl group which may be substituted; each of W¹, W², W³ and W⁴ whichare independent of one another, is an oxygen atom or a sulfur atom; andm is 0 or 1, excluding a case where one of X and Y is a —COCF₂X¹ group(wherein X¹ is a hydrogen atom, a halogen atom, an alkyl group or ahaloalkyl group), and the other is a —COCF₂X² group (wherein X² is ahydrogen atom, a halogen atom, an alkyl group, a haloalkyl group or analkylcarbonyl group), a —COOX³ group (wherein X³ is an alkyl group whichmay be substituted or a phenyl group which may be substituted) or a—COX⁴ group (wherein X⁴ is an alkyl group, a haloalkyl group, an alkenylgroup, an alkynyl group, a phenyl group which may be substituted, afuranyl group or a naphthyl group).
 2. The therapeutic or preventiveagent for digestive system diseases according to claim 1, wherein X is a—CW¹R¹ group or a —C(═W¹)W²R³ group and Y is a —SO₂R⁹ group.
 3. Thetherapeutic or preventive agent for digestive system diseases accordingto claim 1, wherein X is a —CW¹R¹ group or a —C(═W¹)W²R³ group, R¹ is analkyl group which may be substituted, an alkenyl group which may besubstituted, a cycloalkyl group which may be substituted, a cycloalkenylgroup which may be substituted, a phenyl group which may be substituted,a tetrahydronaphthyl group which may be substituted, an indanyl groupwhich may be substituted, a furanyl group which may be substituted or athienyl group which may be substituted, R³ is an alkyl group which maybe substituted, Y is a —SO₂R⁹ group, and R⁹ is an alkyl group which maybe substituted, an alkenyl group which may be substituted, a cycloalkylgroup which may be substituted, a cycloalkenyl group which may besubstituted or a phenyl group which may be substituted.
 4. Thetherapeutic or preventive agent for digestive system diseases accordingto claim 1, wherein X is a —CW¹R¹ group or a —C(═W¹)W²R³ group, R¹ is analkyl group, a haloalkyl group, an alkoxycarbonyl alkyl group, analkenyl group, a haloalkenyl group, an alkenyl group substituted with athienyl group, a cycloalkyl group, a cycloalkyl group substituted with ahalogen atom, a phenyl group, a phenyl group substituted with a halogenatom, a phenyl group substituted with an alkyl group or a haloalkylgroup, a phenyl group substituted with an alkoxy group or a haloalkoxygroup, a tetrahydronaphthyl group, an indanyl group, a furanyl group ora thienyl group, R³ is an alkyl group or a haloalkyl group, Y is a—SO₂R⁹ group, and R⁹ is an alkyl group, a haloalkyl group, a phenylgroup, a phenyl group substituted with a halogen atom, a phenyl groupsubstituted with an alkyl group or a haloalkyl group, or a phenyl groupsubstituted with an alkoxy group or a haloalkoxy group.
 5. Thetherapeutic or preventive agent for digestive system diseases accordingto claim 1, wherein X is an alkoxycarbonyl alkylcarbonyl group, analkenylcarbonyl group, an alkenylcarbonyl group substituted with athienyl group, a cycloalkylcarbonyl group, an indanylcarbonyl group, afurancarbonyl group, a thiophenecarbonyl group, atetrahydronaphthylcarbonyl group or a benzoyl group which may besubstituted with a halogen atom or a haloalkyl group, and Y is analkylsulfonyl group.
 6. The therapeutic or preventive agent fordigestive system diseases according to claim 1, wherein X is acycloalkylcarbonyl group, a furancarbonyl group or a benzoyl group whichmay be substituted with halogen, and Y is an alkylsulfonyl group.
 7. Thetherapeutic or preventive agent for digestive system diseases accordingto claim 1, wherein the diaminotrifluoromethylpyridine derivative isN-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide,N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-4-fluorobenzamide,N-(2-isopropylsulfonylamino-5-trifluoromethyl-3-pyridyl)-3-fluorobenzamide,N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-2-furancarboxamideorN-(2-isopropylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclopentanecarboxamide.8. The therapeutic or preventive agent for digestive system diseasesaccording to claim 1, wherein the diaminotrifluoromethylpyridinederivative isN-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide.